The discovery of insulin and its clinical application resulted in drastic progress in the treatment of diabetes. Life sustention of the patients with diabetes--which had been a deadly disease until then--was strikingly improved. However, the therapy for chronic complications of diabetes has become a new problem.
The therapy for diabetes aims at prevention of such chronic complications, and from a practical standpoint consists of a further control of blood glucose and a direct therapy of complications. The major chronic complications of diabetes are known to be neuropathy, nephropathy, ophthalmopathy, arteriosclerosis and the like (David M. et al., N. Engl. J. Med., 328, p.1676-1685(1993)).
Various factors have been considered to be responsible for the onset and progression of chronic complications of diabetes. For example, there are known an abnormal sorbitol metabolism theory wherein activity promotion of sorbitol-producing polyol metabolitic pathway is the cause (Gabbay K. H. et al., N. Engl. J. Med. 288, p.831-837(1973)), a circulatory disorder theory wherein causative factor is a decreased blood flow due to angiopathy (Dyck P. J. et. al., Proc. Natl. Acad. Sci. USA, 82, p.2513-2517 (1985)), a theory attributing the disease to a compound produced by non-enzymatic binding reaction of protein and reducing glucose (AGE: advanced glycation endproduct) (Brownlee M. et al., N. Engl. J. Med. 318, p.1315-1321 (1988)) and the like. Based on each hypothesis, an aldose reductase inhibitor and lipoprostaglandin E1 have been developed, and an AGE production inhibitor is under development
The diabetic patients show promoted platelet aggregation, and the mechanism thereof has been known to be the promotion of biosynthesis of thromboxane (hereinafter abbreviated as TX) A2 due to hypoglycemia. This is considered to be one of the pathogens of diabetic chronic complications (Giovanni Davi M. D. et al., N. Engl. J. Med. 322, p.1769-1774 (1990)). Thus, lipoprostaglandin E1 (hereinafter sometimes to be referred to as Lipo PGE1) having peripheral circulation improving action or platelet aggregation inhibitory action, 6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyryl (cilostazol) and 6-[4-(R)-chlorophenylsulfonamidol-1-(3-pyridylmethyl)pyrrolidin-2(S)-yl)-5 -(Z)-hexenoic acid.hydrochloride (investigational numer: KDI-792) having TXA2 receptor antagonistic/synthesis inhibitory activity have been under development as agents for the prophylaxis and treatment of diabetic complications.
On the other hand, Japanese Patent Examined Publication No. 41143/1993 discloses 4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid having pharmacological activities such as strong TXA2 biosynthesis inhibitory activity, platelet aggregation inhibitory action, vasodilating action and the like, which is useful for the prophylaxis and treatment of thrombosis, cerebral hemorrhage, myocardial infarction, acute cardiac death, angina pectoris, hypertension, asthma, nephritis and the like, an optically active compound and a pharmaceutically acceptable salt thereof. Nevertheless, it is not known that these compounds act as agents for the prophylaxis and treatment of diabetic complications.
Under the circumstances, the development of a new therapeutic agent that acts directly on chronic complications of diabetes for the prophylaxis and treatment of diabetes, which is capable of providing a better quality of life has been desired.
The Lipo PGE 1, cilostazol, KDI-792 and the like, which are under development as agents for the prophylaxis and treatment of diabetic complications based on the above-mentioned peripheral circulation improving activity, platelet aggregation inhibitory activity and TXA2 receptor antagonistic/synthesis inhibitory activity, all exhibit only a short duration of activity and require 2 to 3 times of administration a day. Considering the quality of life of the patients with diabetes, they are remotely sufficient.
The present inventors have confirmed that sodium ozagrel [sodium (E)-p-(imidazol-1-ylmethyl)cinnamate] having TXA2 synthesis inhibitory activity suppresses promotion of biosynthesis of TXA2 in rats with diabetes, but does not improve decreased tail nerve conduction velocity. This suggests that not every TXA2 synthesis inhibitor is effective for diabetic complications.